POS0498 MOLECULAR DOCKING AND PHARMACOLOGICAL ANALYSIS OF ALPHA-PHELLANDRENE IN CHRONIC PAIN: THE ROLE OF SEROTONINERGIC SYSTEM
Authors: Y. M. D. S. Pires, J. T. Ciecilinsky, L. D. S. Gomes, F. D. A. Oliveira, F. R. D. C. Almeida
Journal: Annals of the Rheumatic Diseases (2022)

Background Pain is an unpleasant sensory and emotional experience that causes human suffering. 1 Its prevalence has increased, as well as the abuse and dependence on strong opioids. 2,3 The α-phellandrene is a terpene that exerts antinociceptive and immunostimulant effects, 4 however, its mechanisms remain to be elucidated. In this way, bioinformatics may assist in developing new therapeutic approaches for pain management. Objectives To investigate the action of a-PHEL in chronic pain, focusing on the role of the serotoninergic system, to develop a new therapeutic tool without the side effects of conventional drugs. Methods Molecular docking is an important method for the investigation of the mechanism of action of natural compounds. It is possible to evaluate the molecular dynamics, elucidating the stability of complexes. The software PyMOL and AutoDock Vina 1.5.7 were used to predict interactions of a-PHEL and 5-HT 2A R. The mechanism of action of a-PHEL in chronic pain was analyzed in vivo as well. The Ethics Committee of UFPI approved this project (protocol n° 305/17). Female Swiss mice (25-30 g) underwent partial sciatic nerve ligation surgery to induce neuropathy. The neuropathic mice (N=6) were pre-treated with 5-HT 2A receptor antagonist Ketanserin (0,3 mg/kg, i.p.) or Saline (10 mL/kg, p.o.). After 20min, they were treated with α-phel (6,25 mg/kg, p.o.) and after 1h they were evaluated by the Von Frey test. Results The serotoninergic system has a complex and important role in pain modulation especially through descending inhibitory pathways. The Molecular docking predicted the positioning of a-PHEL in the 5-HT 2A R, aiding the understanding of its biological activity. The analysis identified 9 key positions for the ligand binding in 5-HT 2A R. The lowest Gibbs free energy ΔG= -6.9 kcal/mol. The negative binding energy indicates a strong and stable bond, therefore, α-PHEL has a high affinity for the receptor (Figure 1). Figure 1. Graphical 3D representation of the binding mode of α-PHEL with 5-HT 2A R. A - The ligand (orange) is shown surrounded by a molecular surface of the receptor (green). B – Representation of the best-scoring docked pose (-6.9 kcal/mol) of a-PHEL (orange). Excellent in vivo therapeutic effects were observed in the animal model of neuropathic pain. Regarding the pharmacological in vivo analysis, the a-PHEL significantly decreased the pain threshold (P&lt;0.05), exhibiting an anti-hypersensitive effect. The inhibition of serotonergic transmission by pretreatment with Ketanserin significantly reduced the antinociceptive effect of a-PHEL in mice. The data indicate that a-PHEL exerts its antinociceptive effect on chronic neuropathic pain model by activation of the 5-HT2AR receptor. Its analgesic effect seems to be mediated by descending inhibitory serotonin system interfering with pain impulse transduction. Conclusion Chronic pain is often resistant to medical treatment and the cheminformatics techniques may facilitate the discovery of new compounds, guiding towards specific molecular targets. The a-PHEL may act as a serotoninergic agonist, reducing mechanical sensitivity. It is a promising compound for chronic pain treatment, with lower cost and fewer adverse effects than opioids. Future investigations are expected to highlight the in-depth effects of the interaction of a-PHEL with other receptor subtypes. References [1]Raja SN, et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain. 2020;161(9):1976-1982. [2]Xie J, et al. Temporal trends of opioid use among incident osteoarthritis patients in Catalonia, 2007-2016: a population-based cohort study. Annals of The Rheumatic Disease. 2020; 79 (sl. 1): 174. [3]Liktor-Busa E, et al. Analgesic Potential of Terpenes Derived from Cannabis sativa . Pharmac Rev. 2021, 73(4):98-126. [4]Pinheiro FR, et al. α-Phellandrene exhibits antinociceptive and tumor-reducing effects in a mouse model of oncologic pain. Tox Appl Pharmacol. 418(1), 2021 Disclosure of Interests None declared.